Highly enantioselective carbon–carbon bond formation by Cu-catalyzed

asymmetric [2,3]-sigmatropic rearrangement: application to the syntheses

of seven-membered oxacycles and six-membered carbocyclesw

Gullapalli Kumaraswamy,*aKadivendi Sadaiah,

aDuggirala Subrahmanya Ramakrishna,

a

Naresh Police,bBalasubramanian Sridhar

cand Jagadeesh Bharatam

b

Received (in Cambridge, UK) 25th June 2008, Accepted 5th August 2008

First published as an Advance Article on the web 17th September 2008

DOI: 10.1039/b810770j

A concise route for the syntheses of enantioenriched functionalized

scaffolds of medium-sized oxacycles and carbocycles employing

the chiral auxiliary-mediated Cu-catalyzed ylide formation/[2,3]-

sigmatropic rearrangement as a key step was developed.

In recent years there has been a resurgence of interest in

therapeutic targets based on the structures of bioactive natural

products.1 Oxacycles and carbocycles possessing pharmaco-

phoric active sites are common structural features of various

biologically active natural products.2 Owing to their biological

activity coupled with complexity, they have become attractive

targets for synthesis. The design and synthesis of enantiomeri-

cally pure medium-sized oxacycles and carbocycles have

attracted a great deal of attention due to the concept of small

molecular entities for drug discovery and development.3 The

strategies that were developed for preparing such molecules

were found to be inadequate.4 Recently, Doyle et al. have

developed an impressive catalytic bis-oxazoline Cu-catalyzed

asymmetric [2,3]-sigmatropic rearrangement of diazoacetate

derived from allyl-substituted 1,2-benzenedimethanol. Despite

their best efforts, the resulting product showed only 65% ee,

thereby restricting the further applicability of this reaction.5 The

erosion in enantioselectivity appears to be due to the flexible

conformations of the 11-membered oxonium ylide transition

state, leading to the product in only moderate enantioselec-

tivity. We reason that steric and electronic factors, which may

stabilize oxonium ylide conformation and its subsequent [2,3]-

sigmatropic rearrangement, could lead to highly enantioselec-

tive carbon–carbon bond formation. Herein, we disclose our

preliminary results relating to this object and its relevance for

the synthesis of medium-sized carbocycles and oxacycles.

Initially, we examined the (R)-phenylethylene glycol tethered

with diazoacetate and methoxy cis-butene 1 (Scheme 1) as a

test substrate. The precursor 1 was prepared in five steps from

(R)-mandelic acid. The Cu-catalyzed6 (5 mol%) reaction of 1

in DCM at reflux temperature led to a diastereomeric mixture

of 2 and 3 in a 6 : 4 ratio (syn : anti) but the diastereomeric

excess was found to be moderate (2, 93% de and 3, 79% de).

Along with 2 and 3, 15% of 4 was also isolated. To identify

another class of auxiliary that would allow highly enantiose-

lective carbon–carbon bond formation, we examined a C2-

symmetric diol tethered with diazoacetate and methoxy cis-

butene 5a as starting material.

The Cu-catalyzed (5 mol%)z reaction of 5a using identical

conditions resulted in 6a and 7a in 68% yieldy with a similar

diastereomeric ratio (dr = 6 : 4 syn : anti) but with a

substantial increase in diastereomeric excess (6a, 99.8% de

and 7a, 99.8% de) (Scheme 2). The diastereomers 6a and 7a

were separated by silica gel column chromatography and their

stereochemical assignment was established by the vicinal

coupling constant to the proton on the methoxy-substituted

carbon (Janti 5.7 Hz 4 Jgauche 3.2 Hz) as well as NOE studies.

In 6a, the presence of strong NOEs (He–Hd, Hd–Hb, Hb–Hi)

and a weak NOE of He–Hb indicates that these are in the same

plane (Fig. 1).

Additionally, a medium range NOE between Hf and OMe

confirms that Ha and Hb are in cis conformation. Whereas, in

7a, the presence of an NOE (Ha–Hf) and (Hb–Hi) indicates

that these protons are nearer, and the absence of an NOE

(Hf–OMe) shows that they are in opposite planes, and hence,

Ha and Hb are in trans conformation.

Scheme 1

aOrganic Division-III, Indian Institute of Chemical Technology,Hyderabad, 500 007, India. E-mail: gkswamy_iict@yahoo.co.in;Fax: +91-40-27193275; Tel: +91-40-27193154

bNMR Division, Indian Institute of Chemical Technology, Hyderabad,500 007, India

c Laboratory of X-ray crystallography, Indian Institute of ChemicalTechnology, Hyderabad, 500 007, Indiaw Electronic supplementary information (ESI) available: Synthesisand analytical data. CCDC reference number 690682. For ESI andcrystallographic data in CIF or other electronic format see DOI:10.1039/b810770j

5324 | Chem. Commun., 2008, 5324–5326 This journal is �c The Royal Society of Chemistry 2008

COMMUNICATION www.rsc.org/chemcomm | ChemComm

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The de values of 6a and 7a were determined by chiral HPLC

analysis in comparison with a racemic mixture. The major syn

isomer 6a and minor anti isomer 7a showed 499.8% de.

The stereochemical outcome of products 6a and 7a could be

rationalised on the basis of the oxonium ylide transition state

of the corresponding 6a* and 7a*, wherein the C2-symmetric

1,2-diphenylethane serves as a template for the formation of

highly enantioselective C–C bond formation (Scheme 3).

Significantly, in contrast to the previous reports,5b no trace

of intramolecular cyclopropanation product was observed in

this transformation.

Further, we prepared the substrates 5b–d and subjected them

to the same protocol. In the case of 5b, only a trace of the

terminal cyclopropanated product was isolated. Substrate 5c

resulted in product 6c (10%) via the expected ylide formation/

[2,3]-sigmatropic rearrangement along with a major unidentified

product (40%). Under otherwise identical conditions, with the

substrate 5d, neither the [2,3]-sigmatropic rearrangement pro-

ducts 6d and 7d nor the cyclopropanated product was formed.

In order to increase the diastereoselectivity, we have evalu-

ated 5a with a spectrum of catalysts such as Rh2(pfb)4 (pfb =

perfluorobutyrate), Rh2(OAc)4, and Rh2(octanoate). To our

surprise only trace of syn product 6a (5–8%) along with 8a

(B30%) were isolated with each of the Rh precursors.

To ascertain chemoselectivity, we have synthesized an allyl-

tethered diazo C2-symmetric substrate 9. The Cu-catalyzed

(5 mol%) diazodecomposition of 9 in DCM at reflux tempera-

ture resulted exclusively in the cyclopropanation product 10 in

50% yield with 499.9% de along with 11 (15%) (Scheme 4).

The relative stereochemistry (S,R) of 10 was confirmed by

X-ray crystallography (Fig. 2).

Finally, the products derived from the [2,3]-sigmatropic

rearrangement were conveniently elaborated to the synthesis

of medium-sized oxacycles and carbocycles. To this end, 6a

was converted to a diol by LAH reduction in THF, and

subsequent protection of the primary alcohol as the TBDMS

ether was followed by removal of the chiral auxiliary in liq.

NH3 at �78 1C which led to 12 (81% from 6a).

The resulting primary alcohol 12 was protected as the

benzyl ether, and subsequent p-toluenesulfonic acid (PTSA)-

assisted cleavage of the TBDMS group furnished 13. Allyla-

tion of primary alcohol 13 with allyl bromide using NaH in

THF afforded 14 (86%). A one-pot RCM/dihydroxylation

sequence followed by acetonide protection of 14 resulted in 15

and 16 (6 : 4) as separable diastereomers in 60% yield.7

Similarly, the diastereomers 17 and 18 were achieved from

7a using an identical sequence of steps as above in an overall

37.6% yield (Scheme 5).8

With a notion to prepare functionalized carbocycles, 13 was

subjected to oxidation to give 19 in 90% yield. A catalytic

allylation9 of 19 led to 20 as a separable diastereomeric

mixture (8 : 2) in 61% isolated yield. The major diastereomer

20 was separated through column chromatography and was

Scheme 2

Fig. 1 NOE study of 6a and 7a.

Scheme 3 Oxonium ylide transition states of 6a and 7a. Fig. 2 ORTEP representation of 10 with 50% probabilty.

Scheme 4 Cu-catalyzed cyclopropanation of 9.

This journal is �c The Royal Society of Chemistry 2008 Chem. Commun., 2008, 5324–5326 | 5325

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subjected to ring-closing metathesis (RCM) reaction employ-

ing a Grubb’s second generation catalyst, furnishing 21, which

has an option for further elaboration by means of various

addition reactions. The diastereomer 22 was generated from

7a following an identical sequence of steps as above in an

overall 42.8% yield (Scheme 6).

In conclusion, we have accomplished a concise enantio-

selective route for the syntheses of functionalized scaffolds of

medium-sized oxacycles and carbocycles employing a chiral

auxiliary-mediated Cu-catalyzed ylide formation/[2,3]-sigma-

tropic as a key step. Additionally, the complementary sense of

enantioenriched molecules of oxacycles has been synthesized

using an antipode of C2-symmetric (S,S)-diol, thus generating

a library of target molecules.10 Further work is under progress

for the synthesis of carbocyclic analogues based on oseltamivir

phosphate, an important anti-influenza drug, as motif.11

Notes and references

z Reaction also proceeded with 1 and 2 mol% of catalyst loading. Theresulting product showed with same dr and de, but slightly decreasedyields were obtained [6a + 7a = 55% (1 mol%), 58% (2 mol%),respectively].y Experimental and spectral data of 6a. A solution of diazoacetate 5a

(1 g, 2.73 mmol) in DCM (60 mL) was added using a syringe pump(12 mL h�1) to tetrakis(acetonitrile)copper(I) hexafluorophosphate(51 mg, 5 mol%) dissolved in DCM (60 mL) under reflux conditionsfor a period of 5 h. After completion of the addition, the resultingreaction mixture was allowed to cool to rt, then the solvent wasremoved under reduced pressure. The crude residue was subjected tocolumn chromatography (silica gel, 100–200 mesh) eluting withhexane–EtOAc (97 : 3) to give 7a (anti) (250 mg, 27%) and 6a (syn)

(380 mg, 41%) including recovered 8a (122 mg, 15%). 6a: solid, mp120 1C, [a]D24 �74.0 (c 0.01, CHCl3);

1H NMR (500 MHz, CDCl3):d 7.29–7.17 (m, 6H), 7.10 (d, J = 6.5 Hz, 2H), 6.98 (d, J = 6.5 Hz,2H), 6.13 (ddd, J1 = 17.0, J2 = 11.0, J3 = 8.7 Hz, 1H), 5.94(d, J = 9.0 Hz, 1H), 5.29–5.26 (m, 2H), 4.37 (d, J = 9.7 Hz, 1H),4.22 (dd, J1 = 6.5, J2 = 11.6 Hz, 1H), 4.16 (d, J = 5.8 Hz, 1H), 3.93(d, J = 10.3 Hz, 1H), 3.51 (s, 3H), 3.30–3.21 (m, 1H); 13C NMR(100 MHz, CDCl3): d 174.1, 137.0, 135.1, 133.7, 128.6, 128.2, 128.0,127.5, 127.3, 118.4, 96.1, 86.9, 80.0, 74.0, 58.4, 50.3. IR (KBr): 3473,3084, 2938, 2890, 1745, 1454, 1209, 1116, 986, 698 cm�1; MS (ESIMS):m/z 338.9 (M + H+), 321, 242, 197; HRMS (ESIMS): Calculated forC21H22O4Na, 361.1415, Found 361.1415.

1 R. M. Wilson and S. J. Danishefsky, Acc. Chem. Res., 2006, 39,539; M. Murata and T. Yasumoto, Nat. Prod. Rep., 2000, 17, 293;A. Ameri, Prog. Neurobiol., 1998, 56, 211; F. J. Schmitz, S. P.Gunasekera, G. Yalamanchili, M. B. Hossain and D. J. Van derHelm, J. Am. Chem. Soc., 1984, 106, 7251; N. Fusetani, T.Sugawara and S. Matsunaga, J. Org. Chem., 1991, 56, 4971.

2 S. E. Denmark, C. S. Regens and T. Kobayashi, J. Am. Chem.Soc., 2007, 129, 2774; A. A. E. El-Zayat, N. R. Ferrighi, T. G.McKenzie, R. S. Byrn, J. M. Cassady, C.-J. Chang and J. L.McLaughlin, Tetrahedron Lett., 1985, 26, 955; K. C. Nicolaou, K.P. Cole, M. O. Frederick, R. J. Aversa and R. M. Deton, Angew.Chem., Int. Ed., 2007, 45, 8875; R. Sakai, H. Kamiya, M. Murataand K. Shimamoto, J. Am. Chem. Soc., 1997, 119, 4112; R. Sakai,T. Koike, M. Sasaki, K. Shimamoto, C. Oiwa, A. Yano, K.Suzuki, K. Tachibana and H. Kamiya, Org. Lett., 2001, 3, 1479.

3 M. Inoue, Chem. Rev., 2005, 105, 4379; I. Nakamura and Y.Yamamoto, Chem. Rev., 2004, 104, 2127; K. Fujiwara, A. Goto,D. Sato, H. Kawai and T. Suzuki, Tetrahedron Lett., 2005, 46,3465; T. Saitoh, T. Suzuki, N. Onodera, H. Sekiguchi, H.Hagiwara and T. Hoshi, Tetrahedron Lett., 2003, 44, 2709; M. T.Crimmins and K. A. Emmitte, Org. Lett., 1999, 1, 2029; J. W.Burton, J. S. Clark, S. Derrer, T. C. Stork, J. G. Bendall and A. B.Holmes, J. Am. Chem. Soc., 1997, 119, 7483; G. Kumaraswamy,M. Padmaja, B. Markondaiah, N. Jena, B. Sridhar and M. UdayaKiran, J. Org. Chem., 2006, 71, 337; G. Kumaraswamy, K.Ankamma and A. Pitchaiah, J. Org. Chem., 2007, 72, 9822.

4 S. V. Pansare and V. A. Adsool, Org. Lett., 2006, 8, 5897; B.Schmidt and A. Biernat, Org. Lett., 2008, 10, 105; M. C. Elliott,J. Chem. Soc., Perkin Trans. 1, 2002, 2301K. Fujiwara, in MarineNatural Products (Topics in Heterocyclic Chemistry), ed. H.Kiyota, Springer-Verlag, Berlin, 2006, vol. 5, p. 97.

5 (a) M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; (b) M.P. Doyle and C. S. Peterson, Tetrahedron Lett., 1997, 38, 5265; (c)M. P. Doyle, C. S. Peterson, M. N. Protopopova, A. B. Marnett, D.L. Parker, Jr, D. G. Ene and V. Lynch, J. Am. Chem. Soc., 1997,119, 8826; (d) M. P. Doyle, C. S. Peterson and D. L. Parker, Jr,Angew. Chem., Int. Ed. Engl., 1996, 35, 1324; (e) M. P. Doyle, V.Bagheri and N. K. Harn, Tetrahedron Lett., 1988, 38, 5119.

6 For this transformation, among the surveyed catalystsCu(CH3CN)4PF6 turned out to be the best. The electropositiveCu attached to a large counter anion appears to be essential toinitiate the reaction. We have also evaluated other Cu sources suchas Cu(OTf)2, CuCl2, Cu(OAc)2, Cu(pivalate)2, Cu(acac)2, CuSO4,and CuI, but none gave the observed product.

7 A. A. Scholte, M. H. An and M. L. Snapper, Org. Lett., 2006, 8,4759; A complete set NOE studies for 15 and 16 was attempted.For details see ESIw.

8 We also attempted the synthesis of functionalized seven-memberedlactones. Unfortunately, compounds A0 and A00 did not undergothe RCM reaction.

.9 A. Yanagisawa, H. Nakashima, A. Ishiba and H. Yamamoto,J. Am. Chem. Soc., 1996, 118, 4723.

10 The preferential conformations of 15, 16, 17, 18, 21, 22 [com-pounds generated using the (R,R)-diol], 6a00, 7a00, 1500 and 1700

[compounds generated using the (S,S)-diol], have been charac-terised by NMR data (see ESIw).

11 M. Shibasaki and M. Kanai, Eur. J. Org. Chem., 2008, 1839.

Scheme 5 Syntheses of functionalized oxacycles.

Scheme 6 Syntheses of functionalized carbocycles.

5326 | Chem. Commun., 2008, 5324–5326 This journal is �c The Royal Society of Chemistry 2008

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